Research Progress on Ferroptosis in Subarachnoid Hemorrhage

Abstract

Early brain injury (EBI) following subarachnoid hemorrhage (SAH) remains a pivotal determinant of patient prognosis. Emerging evidence identifies ferroptosis as a central mechanism driving neuronal damage post‑SAH. The breakdown of hemoglobin/heme precipitates intracerebral labile iron overload, while the hypoxic microenvironment triggers ferritinophagy, further destabilizing iron homeostasis. This iron metabolic derangement, coupled with phospholipid remodeling mediated by enzymes such as ACSL4 and LPCAT3, leads to the accumulation of peroxidation‑prone polyunsaturated fatty acids within neuronal membranes. Oxidative stress induced by SAH compromises the critical System Xc⁻/GSH/GPX4 axis and the parallel FSP1/CoQ10 pathway, culminating in unchecked lipid peroxidation. Moreover, ferroptosis not only precipitates direct neuronal death but also releases damage‑associated molecular patterns (DAMPs) that activate microglia, establishing a “ferroptosis‑neuroinflammation” positive feedback loop that exacerbates cerebral injury. In response to this pathology, ferroptosis inhibitors such as ferrostatin‑1 and liproxstatin‑1, alongside natural agents like puerarin and melatonin, have demonstrated neuroprotective efficacy. Circulating ferroptosis markers (ACSL4, SLC7A11, GPX4) also show promise for prognostic evaluation. In summary, targeting the ferroptosis pathway offers novel therapeutic avenues for managing EBI after SAH.